Submissions for variant NM_000251.3(MSH2):c.5C>T (p.Ala2Val)

gnomAD frequency: 0.00001  dbSNP: rs587778521

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000168363	SCV000219053	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-20	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2 of the MSH2 protein (p.Ala2Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of MSH2-related conditions (PMID: 23729658). ClinVar contains an entry for this variant (Variation ID: 134840). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000512708	SCV000293266	uncertain significance	not provided	2023-05-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in a healthy European individual under age 50 undergoing whole genome sequencing (Bodian et al., 2014); This variant is associated with the following publications: (PMID: 23729658, 26951660, 30798936, 33357406, 22814378, 18822302, 21120944, 24728327)
Counsyl	RCV000410801	SCV000487976	uncertain significance	Lynch syndrome 1	2015-12-09	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000121557	SCV000601487	uncertain significance	not specified	2017-02-24	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000512708	SCV000608935	uncertain significance	not provided	2017-03-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000561626	SCV000662316	likely benign	Hereditary cancer-predisposing syndrome	2021-07-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000561626	SCV000685106	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-15	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 2 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 2/215642 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Myriad Genetics, Inc.	RCV000410801	SCV004018344	likely benign	Lynch syndrome 1	2023-03-21	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV000410801	SCV004196321	uncertain significance	Lynch syndrome 1	2023-08-08	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997346	SCV004826160	uncertain significance	Lynch syndrome	2023-09-18	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 2 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 2/215642 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
ITMI	RCV000121557	SCV000085751	not provided	not specified	2013-09-19	no assertion provided	reference population